Preparation of pharmaceutically acceptable atorvastatin salts in non-crystalline forms

ABSTRACT

Non-crystalline, in particular amorphous, pharmaceutically acceptable atorvastatin salts, especially the calcium salt, are prepared from atorvastatin lactone or from a compound of formula (I)  
                 
 
     where A denotes a common protecting group or separate protecting groups for the two hydroxy groups, and B denotes a carboxylic acid protecting group, without the need of prior formation of atorvastatin lactone, the crystalline form of the atorvastatin salt, or a mixture of amorphous and crystalline forms of the atorvastatin salt. Pharmaceutical formulations are prepared from these salts.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part of InternationalApplication No. PCT/IB02/00161, filed Jan. 22, 2002 and designating theUnited States; which claims the priority of Slovenian Application No.P-01100010, filed Jan. 23, 2001. Each of these applications isincorporated into this application by reference.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] This invention relates to a method of preparing pharmaceuticallyacceptable atorvastatin salts in noncrystalline form.

[0004] 2. Description of the Related Art

[0005] Atorvastatin calcium (USAN: the INN for the salt isatorvastatin), the substance having the chemical name[(R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-(phenylamino)carbonyl-1H-pyrrole-1-heptanoicacid calcium salt (2:1) and the formula

[0006] is known as an HMG-CoA reductase inhibitor and is used as anantihypercholesterolemic agent.

[0007] Atorvastatin lactone is the compound of the formula

[0008] Processes for the preparation of atorvastatin and its salts,atorvastatin lactone, and key intermediates, are disclosed in U.S. Pat.Nos. 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,155,251;5,216,174; 5,245,047; 5,248,793; 5,280,126; 5,342,952; and 5,397,792.Atorvastatin is usually prepared as the calcium salt since this enablesatorvastatin to be conveniently formulated in pharmaceuticalformulations, for example, in tablets, capsules, powders and the likefor oral administration.

[0009] Atorvastatin calcium can exist in amorphous form or in one ofseveral crystalline forms (Form I, Form II, Form III and Form IV), whichare disclosed in International Publications Nos. WO 97/3958 (U.S. Pat.No. 6,121,461) and WO 97/3959 (U.S. Pat. No. 5,969,156). It is knownthat the amorphous forms of a number of pharmaceutical substancesexhibit different dissolution characteristics and bioavailabilitypatterns compared to the crystalline forms (Konno T., Chem. Pharm.Bull., 1990, 38:2003-2007). For some therapeutic indications thebioavailability is one of the key parameters determining the form of thesubstance to be used in a pharmaceutical formulation. Since processesfor the crystallization and the preparation, respectively, of theamorphous substance are sometimes difficult, and sometimes affordamorphous-crystalline mixtures, that is, a crystalline form instead ofan amorphous form, there is a constant need for processes which enablethe preparation of a non-crystalline form without simultaneousformulation of crystalline forms, that is, which will enable theconversion of the crystalline form into the non-crystalline form.

[0010] Atorvastatin calcium is a substance which is very slightlywater-soluble, and it has been found that the crystalline forms are lessreadily soluble than the amorphous form, which may cause problems in thebioavailability of atorvastatin in the body. It has been found that theproduction of amorphous atorvastatin calcium according to the previouslydisclosed processes was not consistently reproducible, and therefore aprocess has been developed for converting the crystalline forms ofatorvastatin calcium (formed in the synthesis of atorvastatin) to theamorphous form. The process is described in International PublicationNo. WO 97/3960 (U.S. Pat. No. 6,087,511) and comprises dissolving acrystalline form of atorvastatin calcium in a non-hydroxylic solvent andremoving the solvent to afford amorphous atorvastatin calcium. Thepreferred non-hydroxylic solvent is selected from the group consistingof tetrahydrofuran and a mixture of tetrahydrofuran and toluene.

[0011] The disadvantage of the above process is primarily use ofnon-nature-friendly solvents. A similar process is described inInternational Publication No. WO 00/71116 and comprises dissolving thecrystalline form of atorvastatin calcium in a non-hydroxylic solvent,such as, for example, tetrahydrofuran. To the solution of atorvastatincalcium is added a nonpolar organic solvent, or the solution ofatorvastatin calcium is added to a nonpolar organic solvent, to allowatorvastatin calcium to precipitate. The formed precipitate is filteredoff.

[0012] Synthesis of amorphous atorvastatin calcium is demanding andaccordingly the cost of the finished product is high.

SUMMARY OF THE INVENTION

[0013] It is an object of this invention to minimize the number ofsynthesis steps in the process for the preparation of pharmaceuticallyacceptable atorvastatin salts in non-crystalline form and in this mannerto improve the yield.

[0014] The present invention provides a process for the conversion of acompound of formula (I)

[0015] where A denotes a common protecting group or separate protectinggroups for the two hydroxy groups, and B denotes a carboxylic acidprotecting group, into a non-crystalline, in particular amorphous,pharmaceutically acceptable atorvastatin salt, especially the calciumsalt, without the need of prior formation of atorvastatin lactone, thecrystalline form of the atorvastatin salt, or a mixture of amorphous andcrystalline forms of the atorvastatin salt.

[0016] In a further aspect, the present invention also provides theconversion of atorvastatin lactone into a non-crystalline, in particularamorphous, pharmaceutically acceptable atorvastatin salt withoutintermediate formation of the atorvastatin salt in crystalline form or amixture of amorphous and crystalline forms.

[0017] In a still further aspect, the present invention also provides aprocess for the preparation of a pharmaceutical formulation containing apharmaceutically acceptable atorvastatin salt, especially the calciumsalt, which has been prepared directly in the non-crystalline, inparticular in the amorphous, form.

BRIEF DESCRIPTION OF THE FIGURE

[0018] The FIGURE shows an X-ray powder diffractogram of atorvastatincalcium obtained by the process of this invention.

DETAILED DESCRIPTION OF THE INVENTION

[0019] Accordingly, the present invention in the first aspect provides aprocess for preparing a pharmaceutically acceptable atorvastatin salt innon-crystalline form, which comprises:

[0020] a) providing a solution in a non-hydroxylic solvent of a compoundof formula (I)

[0021]  where

[0022] A denotes a common protecting group or separate protecting groupsfor the two hydroxy groups, and

[0023] B denotes a carboxylic acid protecting group;

[0024] b) deprotecting the two hydroxy groups;

[0025] c) deprotecting the carboxylic acid group; where steps b) and c)may be performed in either order;

[0026] d) optionally concentrating the solution to not more than halfits initial volume;

[0027] e) adding water to the optionally concentrated solution;

[0028] f) adding a solvent which is slightly miscible or immiscible withwater and in which the pharmaceutically acceptable atorvastatin salt isinsoluble or practically insoluble, in an amount not less than the watervolume added in step e);

[0029] g) optionally mixing the phases, and then separating the twophases;

[0030] h) neutralizing the aqueous phase;

[0031] i) converting atorvastatin in the aqueous phase to thepharmaceutically acceptable salt; and

[0032] j) precipitating the pharmaceutically acceptable atorvastatinsalt in non-crystalline form.

[0033] The compound of formula (I) is preferably a compound of formula(II)

[0034] where

[0035] R¹ and R² are independently hydrogen, alkyl of from one to threecarbon atoms, or phenyl, or R¹ and R² together form an alkylene of fouror five carbon atoms, and

[0036] B is

[0037] a) OR³ where R³ is straight or branched chain alkyl of from oneto eight carbon atoms, cycloalkyl of from three to six carbon atoms, oraralkyl (straight or branched chain alkyl of from one to four carbonatoms substituted with a phenyl group that is optionally substitutedwith up to three straight or branched chain alkyl groups of from one tofour carbon atoms), preferably tert-butyl, tert-amyl, orα,α-dimethylbenzyl, or

[0038] b) NR⁴R⁵ where R⁴ and R⁵ are independently straight or branchedchain alkyl of from one to ten carbon atoms, cycloalkyl of from three toseven carbon atoms (such as cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl), aryl or aralkyl (such as phenyl or benzyl), or R⁴ and R⁵together form an alkylene of from four to six carbon atoms of which oneor two carbon atoms may be replaced by hetero atoms (such as O),optionally substituted with one or more alkyl groups of from one to fourcarbon atoms, such as —(CH₂)₄—, —(CH₂)₅—, —CH(R⁶)—(CH₂)₃—,—CH(R⁶)—(CH₂)₄—, —CH(R⁶)—(CH₂)₂—CH(R⁶)—, —CH(R⁶)—(CH₂)₂—CH(R⁶)—,—CH₂CH₂OCH₂CH₂—, —CH(R⁶)—CH₂OCH₂CH₂—, and —CH(R⁶)—CH₂OCH₂—CH(R⁶)—, whereR⁶ is straight or branched chain alkyl of from one to four carbon atoms.

[0039] A particular example of a compound of formula ( ) is the compoundof formula (III)

[0040] The preparation of the compounds of formulae (I), (II), and (III)is described in European Published Application No. 0 330 172 (U.S. Pat.No. 5,003,080) and International Publication No. WO 94/20492 (U.S. Pat.No. 5,298,627), these documents being incorporated herein by reference.

[0041] In the second aspect, this invention further relates to a processfor the conversion of atorvastatin lactone into a pharmaceuticallyacceptable atorvastatin salt in non-crystalline form, which comprisesproviding the atorvastatin lactone in a non-hydroxylic solvent, openingthe lactone ring, and then performing steps d) to j) of the first aspectof the invention are performed.

[0042] In other words, the process of the second aspect of thisinvention comprises:

[0043] a′) providing a solution of atorvastatin lactone in anon-hydroxylic solvent;

[0044] b′) opening the lactone ring;

[0045] c′) optionally concentrating the solution to not more than halfits initial volume;

[0046] d′) adding water to the optionally concentrated solution;

[0047] e′) adding a solvent which is slightly miscible or immisciblewith water and in which the pharmaceutically acceptable atorvastatinsalt is insoluble or practically insoluble, in an amount not less thanthe water volume added in step d′);

[0048] f′) optionally mixing the phases, and then separating the twophases;

[0049] g′) neutralizing the aqueous phase;

[0050] h′) converting atorvastatin in the aqueous phase to thepharmaceutically acceptable salt; and

[0051] i′) precipitating the pharmaceutically acceptable atorvastatinsalt in non-crystalline form.

[0052] The preparation of atorvastatin lactone is also described inEuropean Published Application No. 0 330 172 (U.S. Pat. No. 5,003,080)and International Publication No. WO 94/20492 (U.S. Pat. No. 5,298,627),these documents being incorporated herein by reference.

[0053] The present invention is described in more detail by referring tothe following embodiments.

[0054] According to the process, the compound of formula (I), especiallythat of formula (II) and in particular that of formula (III), isprovided in solution in a non-hydroxylic solvent. The solution may beprovided in the course of the synthesis of the compound, or the compoundmay be dissolved in an appropriate amount, for example from 100 mL to300 mL per 7 g of the compound of formula (I) (a maximum concentrationof the compound of formula (I) is 80 g/L), of a non-hydroxylic solventsuch as, for example, tetrahydrofuran, 1,4-dioxane, acetone, ethylacetate or a mixture of these solvents; or mixtures of mentionedsolvents with toluene, n-heptane, n-hexane, acetonitrile in the volumeratio from 1:0.01 to 1:1.0. Then, the deprotection of the two hydroxygroups in the side-chain (in the 3-and 5-positions) of the compound isperformed, which can conveniently be done by the addition of an acidsuch as a mineral acid, for example diluted hydrochloric acid orsulfuric acid, trifluoroacetic acid, formic acid, propanoic acid, orpara-toluenesulfonic acid. The molar ratio of the added acid to thecompound of formula (I), (II), or (III) is from 1:0.05 to 1:0.2 (formonoprotic acids), preferably from 1:0.09 to 1:0.1. The resultingsolution is kept, preferably while being mixed by stirring, agitating orshaking the solution, at a temperature of from 5° C. to 40° C.,preferably at a room temperature so that the compound (1), (II) or(III), respectively, is no longer detectable by thin-layerchromatography (TLC). Then, the deprotection of the carboxylic acidgroup (removal of moiety B such as R³, e.g., tert-butyl), is carriedout, which can conveniently be done by adding an appropriate base suchas an alkali metal hydroxide or alkaline earth metal hydroxide, forexample sodium hydroxide, potassium hydroxide, lithium hydroxide, bariumhydroxide and the like, sodium or potassium hydroxide being preferred,to the solution to adjust the pH of the solution to from 8 to 13,preferably from 9 to 12. The resulting solution is kept, preferablywhile being mixed by stirring, agitating or shaking the solution, at atemperature of from 5° C. to 40° C., preferably at room temperature, sothat hydroxy group deprotected, carboxylic acid group protected compoundis no longer detectable by thin-layer chromatography (TLC).

[0055] The solution is then optionally concentrated, for example byevaporation in vacuo, to not more than half of its initial volume,preferably from 15% to 50% of the initial volume, and more preferably toabout 25% of the initial volume. The optionally concentrated solution isthen diluted with water, preferably with a volume from 0.2-fold to5-fold, e.g. from 0.6-fold to 3-fold, such as 0.6-fold to 1.5-fold, thatof the volume of the optionally concentrated solution. To this solutionis added a solvent which is slightly miscible or immiscible with waterand in which the desired atorvastatin salt, such as atorvastatincalcium, is insoluble or practically insoluble (i.e. in which thesolubility of the atorvastatin salt is not more than 0.1 mg/mL at 25°C.), using about the same or a higher volume than the previously addedwater volume, preferably from 1-fold to 5-fold, and more preferably2-fold to 3-fold, of the previously added water volume. Examples ofsuitable solvents include hexane, heptane, cyclohexane, ether,diisopropyl ether, and the like. Preferably, the resulting solution isvigorously mixed, for example by stirring, agitating or shaking, andsubsequently the phases are separated. Then, the aqueous phase ispreferably rapidly stirred, agitated or shaken while an acid, e.g. amineral acid as mentioned above such as hydrochloric acid, is carefullyadded to neutralize the solution, preferably adjusting the pH of theaqueous phase to from 6.5 to 8, more preferably to from 6.8 to 7.5.

[0056] Then, the atorvastatin so obtained in its dihydroxy carboxylicacid form is converted to a pharmaceutically acceptable salt form. Themost preferred salt form is the calcium salt. This may be carried out byheating the resulting neutralized aqueous solution to a temperature offrom 30° C. to 40° C., preferably at about 35° C. To this solution,which is rapidly mixed by stirring, agitation or shaking, is added afrom 0.05M to 0.5M, preferably from 0.1M to 0.3M, aqueous solution of asalt of the desired cation, which is correspondingly preheated to from30° C. to 40° C., preferably at about 35° C. In order to obtain thepreferred calcium salt form of atorvastatin, a suitable calcium salt,preferably calcium acetate, calcium citrate, calcium oxalate, calciumchloride or calcium iodide, is used. After the completed addition, themixture is preferably kept, suitably under a mixing operation likestirring, agitating or shaking, for a suitable period, for example forfrom 0.5 hour to 3 hours and preferably for about from 1 hour to 2hours, at a temperature of from 10° C. to 30° C., preferably from 20° C.to 25° C.

[0057] Then, a precipitate of the atorvastatin salt is formed. To thisend, the solution may be cooled to a lower temperature, for example to atemperature of from 2° C. to 15° C., preferably from 4° C. to 10° C. Inplace of cooling the solution, the atorvastatin salt, e.g. atorvastatincalcium, may also be precipitated by the addition of a water-miscibleorganic solvent in which the atorvastatin salt is slightly soluble orpractically insoluble.

[0058] As a further alternative, the atorvastatin salt, e.g.atorvastatin calcium, may be precipitated by concentrating the solution,for example, in a vacuum evaporator.

[0059] To give the atorvastatin salt, e.g. atorvastatin calcium, in thedesired non-crystalline form, the formed precipitate may be obtained byappropriate means and, thus, may be filtered, rinsed with water anddried.

[0060] In case the starting substance is atorvastatin lactone, thelactone is correspondingly provided in solution. Likewise, the solutionmay be provided in the course of the synthesis of the lactone, or thelactone may be dissolved in an appropriate amount, for example from 100mL to 300 mL per 8.5 g of the lactone, of a non-hydroxylic solvent suchas, for example, tetrahydrofuran.

[0061] Then, the lactone ring is opened, which is suitably done byadding a base, for example an alkali metal or alkaline earth metalhydroxide as mentioned above such as NaOH. The molar ratio of the addedbase to lactone is from 1:0.2 to 1:0.6, preferably from 1:0.29 to1:0.57. The resulting solution is heated to an appropriate temperature,suitably to from 40° C. to 60° C. and preferably to about 50° C., andmaintained at this temperature for a suitable period until the lactoneis no longer detectable by TLC.

[0062] Subsequently, the solution is concentrated and further processedas described above for the preparation of the non-crystalline substancefrom compound (I) using steps d) to j) described above.

[0063] According to the third aspect of the present invention, theprocess for the preparation of a pharmaceutical formulation containingan atorvastatin salt, preferably atorvastatin calcium, in anon-crystalline form comprises preparing the atorvastatin salt in anon-crystalline form from either the compound of formula (I), morespecifically of formulae (II) or (III), or from the lactone, and mixingthe thus prepared non-crystalline atorvastatin salt with apharmaceutically acceptable carrier in a conventional manner.Preferably, a non-crystalline atorvastatin calcium formulation isprepared. The pharmaceutical formulation is generally solid in the formof tablets, capsules, powders and the like for oral administration.

[0064] The pharmaceutical formulation thus prepared may include, inaddition to the thus directly prepared pharmaceutically acceptableatorvastatin salt in non-crystalline form, in particular non-crystallineatorvastatin calcium, one or more fillers, such as microcrystallinecellulose, lactose, sugars, starches, modified starch, mannitol,sorbitol and other polyols, dextrin, dextran and maltodextrin, calciumcarbonate, calcium phosphate and/or hydrogen phosphate, calcium sulfate,one or more binders, such as lactose, starches, modified starch,dextrin, dextran and maltodextrin, microcrystalline cellulose, sugars,polyethylene glycols, hydroxypropyl cellulose, hydroxypropylmethylcellulose, ethylcellulose, hydroxyethyl cellulose,methylcellulose, carboxymethyl cellulose, gelatin, acacia gum,tragacanth, polyvinylpyrrolidone, magnesium aluminum silicate, one ormore disintegrating agents such as croscarmellose sodium, cross-linkedpolyvinylpyrrolidone, cross-linked carboxymethylstarch, starches andmicrocrystalline cellulose, magnesium aluminum silicate, polyacrylinpotassium, one or more different glidants such as magnesium stearate,calcium stearate, zinc stearate, calcium behenate, sodium stearylfumarate, talc, magnesium trisilicate, stearic acid, palmitic acid,carnauba wax, silicon dioxide, one or more buffering agents such assodium or potassium citrate, sodium phosphate, dibasic sodium phosphate,calcium carbonate, hydrogen phosphate, phosphate, or sulfate, sodium ormagnesium carbonate, sodium ascorbate or benzoate, sodium or potassiumhydrogen carbonate or lauryl sulfate, or mixtures of such bufferingagents.

[0065] If required, the formulation may also include surfactants andother conventional components for solid, pharmaceutical formulationssuch as coloring agents, lakes, aromas and adsorbents. As surfactantsthe following may be used: ionic surfactants, such as sodium laurylsulfate or non-ionic surfactants such as different poloxamers(polyoxyethylene and polyoxypropylene copolymers), natural orsynthesized lecithins, esters of sorbitan and fatty acids (such asSpan®, manufactured by Atlas Chemie), esters of polyoxyethylenesorbitanand fatty acids (such as Tween®, manufactured by Atlas Chemie),polyoxyethylated hydrogenated castor oil (such as Cremophor®,manufactured by BASF), polyoxyethylene stearates (such as Brij®,manufactured by Atlas Chemie), dimethylpolysiloxane, or any combinationof the above mentioned surfactants.

[0066] If the pharmaceutical formulation is in the form of coatedtablets, the coating may be prepared from at least one film-former suchas hydroxypropyl methylcellulose, hydroxypropyl cellulose, at least oneplasticizer such as polyethylene glycols, dibutyl sebacate, triethylcitrate, and other pharmaceutical auxiliary substances conventional forfilm coatings, such as pigments, fillers and others.

[0067] The pharmaceutical formulation may be prepared by conventionalmethods known to those skilled in the art.

[0068] The present invention is illustrated but in no way limited by thefollowing examples.

EXAMPLE 1

[0069] 4.37 g (6.7 mmol) of compound III was dissolved in 200 mL oftetrahydrofuran, 15 mL of 10% HCl was added, and the solution wasstirred at room temperature for 15 hours. 3.6 g (90 mmol) of solid NaOHwas added to this solution, and the solution stirred for an additional30 hours. The solution was concentrated by vacuum evaporation to 50 mL.50 mL of water and 80 mL of hexane were added. The phases wereseparated, and to the rapidly agitated aqueous phase 5M HCl was addedcarefully to a pH of 7.0-7.5. The solution was heated to 35° C., and0.76 g (4.3 mmol) Ca(OAc)₂.xH₂O in 20 mL of water, preheated to 35° C.,was added to the agitated solution. After the completed addition, thesolution was stirred for additional 1 hour at room temperature and thenplaced in a refrigerator for 2 hours. The formed precipitate wasfiltered, rinsed with water (2×20 mL) and dried at 40° C. for 18 hoursto give 3.75 g of non-crystalline atorvastatin calcium.

EXAMPLE 2

[0070] 3.00 g of compound III was dissolved in 140 mL oftetrahydrofuran, 10 mL of 10% HCl was added, and the solution wasstirred at room temperature. 3.6 g of solid NaOH was added to thissolution, and the solution was stirred for 30 hours. The solution wasconcentrated by vacuum evaporation to 20%-25% of its initial volume.Then the same amount of water, and a 1.6-fold amount of hexane, as thevolume of the remaining concentrated solution were added. The phaseswere separated and to the rapidly agitated aqueous phase 5M HCl wasadded carefully to a pH to 7.0. The solution was heated to 35° C. and0.76 g Ca(OAc)₂.xH₂O in 20 mL of water, preheated to 35° C., was addedto the agitated solution. After the completed addition, the solution wasstirred for an additional 1 hour at room temperature and then placed ina refrigerator for 2 hours. The formed precipitate was filtered, rinsedwith water, and dried at 40° C. for 18 hours to give 2.23 g ofnon-crystalline atorvastatin calcium.

[0071] The obtained non-crystalline atorvastatin calcium has the X-raypowder diffractogram substantially that shown in the FIGURE. The X-raypowder diffraction pattern was collected on a Philips PW1710diffractometer in reflection geometry. The instrument was regularlycalibrated with a silicon standard. The sample was not ground before themeasurement. A standard Philips back-loading sample holder was used.Sample storage, mounting, and data collection were done at roomtemperature. Instrumental parameters were: CuK_(α) radiation (30 mA, 40kV, λ=1.5406 Å, variable divergence slit (approx. 12×16 mm irradiatedarea), 0.4 mm receiving slit, graphite monochromator on the secondaryside, scintillation counter. Data collection parameters were: 2θrangefrom 4° to 37°, step scan mode in steps of 0.04° 2θ, integration time 1second at each step.

We claim:
 1. A process for preparing a pharmaceutically acceptableatorvastatin salt in non-crystalline form, which comprises: a) providinga solution in a non-hydroxylic solvent of a compound of formula (I)

 where A denotes a common protecting group or separate protecting groupsfor the two hydroxy groups, and B denotes a carboxylic acid protectinggroup; b) deprotecting the two hydroxy groups; c) deprotecting thecarboxylic acid group; where steps b) and c) may be performed in eitherorder; d) optionally concentrating the solution to not more than halfits initial volume; e) adding water to the optionally concentratedsolution; f) adding a solvent which is slightly miscible or immisciblewith water and in which the pharmaceutically acceptable atorvastatinsalt is insoluble or practically insoluble, in an amount not less thanthe water volume added in step e); g) optionally mixing the phases, andthen separating the two phases; h) neutralizing the aqueous phase; i)converting atorvastatin in the aqueous phase to the pharmaceuticallyacceptable salt; and j) precipitating the pharmaceutically acceptableatorvastatin salt in non-crystalline form.
 2. The process of claim 1where the compound of formula (I) is a compound of formula (II)

where R¹ and R² are independently hydrogen, alkyl of from one to threecarbon atoms, or phenyl, or R¹ and R² together form an alkylene of fouror five carbon atoms, and B is a) OR³ where R³ is straight or branchedchain alkyl of from one to eight carbon atoms, cycloalkyl of from threeto six carbon atoms, or aralkyl, or b) NR⁴R⁵ where R⁴ and R⁵ areindependently straight or branched chain alkyl of from one to ten carbonatoms, cycloalkyl of from three to seven carbon atoms, or R⁴ and R⁵together form an alkylene of from four to six carbon atoms of which oneor two carbon atoms may be replaced by hetero atoms, optionallysubstituted with one or more alkyl groups of from one to four carbonatoms.
 3. The process of claim 1 where the compound of formula (I) is acompound of formula (III)


4. The process of claim 1 where step b) comprises adding an acid andmaintaining the solution at from 5 C to 40° C. with optional mixing. 5.The process of claim 1 where step c) comprises adding a base to adjustthe pH of the solution to from 8 to 13 and maintaining the solution atfrom 5 C to 40° C. with optional mixing.
 6. The process of claim 1 wherestep d) comprises concentrating the solution to from 15% to 50% of itsinitial volume.
 7. The process of claim 1 where step e) comprises addingwater in 0.2-fold to 5-fold relative to the volume of the optionallyconcentrated solution.
 8. The process of claim 1 where step e) comprisesadding water in 0.6-fold to 1.5-fold relative to the volume of theoptionally concentrated solution.
 9. The process of claim 1 where stepf) comprises adding the solvent in 1-fold to 5-fold relative to thewater volume previously added in step e).
 10. The process of claim 1where step h) comprises adding an acid to the aqueous phase to adjustits pH to from 6.5 to
 8. 11. The process of claim 1 where step i)comprises heating the neutralized aqueous solution to from 30° C. to 40°C., and then adding a 30° C. to 40° C. aqueous solution of a salt of thepharmaceutically acceptable cation.
 12. The process of claim 11 where,after the addition of the salt, the solution is mixed at a temperatureof from 10° C. to 30° C.
 13. The process of claim 1 where thepharmaceutically acceptable salt is the calcium salt.
 14. The process ofclaim 1, where step j) comprises adjusting the temperature of thesolution to from 2° C. to 15° C. to precipitate the pharmaceuticallyacceptable atorvastatin salt in non-crystalline form.
 15. The process ofclaim 1 where step j) comprises adding a water-miscible organic solventin which the pharmaceutically acceptable atorvastatin salt ispractically insoluble or insoluble.
 16. A process for preparing apharmaceutical formulation containing a pharmaceutically acceptableatorvastatin salt in non-crystalline form, which comprises: (1)preparing a pharmaceutically acceptable atorvastatin salt innon-crystalline form by the process of claim 1; and (2) mixing thethus-prepared pharmaceutically acceptable atorvastatin salt innon-crystalline form with a pharmaceutically acceptable carrier.
 17. Theprocess of claim 16 where the pharmaceutically acceptable salt is thecalcium salt.
 18. A process for preparing a pharmaceutically acceptableatorvastatin salt in non-crystalline form, which comprises: a′)providing a solution of atorvastatin lactone in a non-hydroxylicsolvent; b′) opening the lactone ring; c′) optionally concentrating thesolution to not more than half its initial volume; d′) adding water tothe optionally concentrated solution; e′) adding a solvent which isslightly miscible or immiscible with water and in which thepharmaceutically acceptable atorvastatin salt is insoluble orpractically insoluble, in an amount not less than the water volume addedin step d′); f′) optionally mixing the phases, and then separating thetwo phases; g′) neutralizing the aqueous phase; h′) convertingatorvastatin in the aqueous phase to the pharmaceutically acceptablesalt; and i′) precipitating the pharmaceutically acceptable atorvastatinsalt in non-crystalline form.
 19. A process for preparing apharmaceutical formulation containing a pharmaceutically acceptableatorvastatin salt in non-crystalline form, which comprises: (1)preparing a pharmaceutically acceptable atorvastatin salt innon-crystalline form by the process of claim 18; and (2) mixing thethus-prepared pharmaceutically acceptable atorvastatin salt innon-crystalline form with a pharmaceutically acceptable carrier.
 20. Theprocess of claim 19 where the pharmaceutically acceptable salt is thecalcium salt.